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ME00928B - New process for synthesis of agomelatine - Google Patents

New process for synthesis of agomelatine

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Publication number
ME00928B
ME00928B MEP-2009-257A MEP25709A ME00928B ME 00928 B ME00928 B ME 00928B ME P25709 A MEP25709 A ME P25709A ME 00928 B ME00928 B ME 00928B
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Montenegro
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formula
compound
synthesis
agomelatine
give
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MEP-2009-257A
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Jean-Pierre Lecouve
Christophe Hardouin
Nicolas Bragnier
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Servier Lab
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Abstract

Postupak za industrijsku sintezu jedinjenja formule (I) :Process for the Industrial Synthesis of Compounds of Formula (I):

Description

Ovaj pronalazak se odnosi na novi postupak dobijanja kristalnog oblika V agomelatina, ili N-[2-(7-metoksi-1-naftil)etil]acetamida, formule (I): This invention relates to a new process for obtaining the crystalline form V agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, formula (I):

Agomelatin ili N-[2-(7-metoksi-1-naftil)etil]acetamid, poseduje korisna farmakološka svojstva. Agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide has useful pharmacological properties.

Ustvari, ima dvostruke osobenosti, da je sa jedne strane agonist receptora melatoninergičnog sistema, a sa druge strane je antagonist receptora 5-HT2C receptora. Ova svojstva mu daju aktivnost u centralnom nervnom sistemu i, preciznije, u lečenju opšte depresije, sezonskih afektivnih poremećaja, poremećaja spavanja, kardiovaskularnih patologija, patologija digestivnog sistema, nesanice i umora kao posledice vremenske razlike, poremećaja apetita i gojaznosti. In fact, it has two characteristics, that on the one hand, it is an agonist of the melatoninergic system receptor, and on the other hand, it is an antagonist of the 5-HT2C receptor. These properties give it activity in the central nervous system and, more precisely, in the treatment of general depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, digestive system pathologies, insomnia and fatigue as a result of time difference, appetite disorders and obesity.

Agomelatin, njegova proizvodnja i njegova upotreba u terapeutske svrhe, opisani su u evropskom patentu EP 0 447 285. Agomelatine, its production and its use for therapeutic purposes are described in European patent EP 0 447 285.

U smislu farmaceutske vrednosti ovog jedinjenja, najvažnije je njegovo dobijanje sa odličnim stepenom čistoće i, naročito, u savršeno reproducibilnom obliku što ima vredne osobenosti omogućavanja njegovog skladištenja u dužim vremenskim periodima bez posebnih zahteva u smislu temperature, svetla, vlažnosti ili nivoa kiseonika. In terms of the pharmaceutical value of this compound, the most important thing is to obtain it with an excellent degree of purity and, especially, in a perfectly reproducible form, which has the valuable characteristics of allowing its storage for longer periods of time without special requirements in terms of temperature, light, humidity or oxygen level.

Patentna prijava EP 1 752 443 opisuje dobro-definisan kristalni oblik agomelatina, kristalni oblik V, koji je opisan svojim dijagramom difrakcije X-zraka praška u nastavku, koji je izmeren upotrebom Siemens D5005 difraktometra (bakarna antikatoda) i izražen u granicama međupovršinske udaljenosti d, Braggovog ugla 2 teta i, relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju): Patent application EP 1 752 443 describes a well-defined crystalline form of agomelatine, crystalline form V, which is described by its X-ray powder diffraction pattern below, which was measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of the interfacial distance d, Bragg angle 2 theta i, relative intensity (expressed as a percentage compared to the most intense line):

Ovaj savršeno definisani kristalni oblik, koji se dobija na reproducibilan način, ima visoko vredne morfološke karakteristike sa, posebno, specifičnom oblasti površine koja je mnogo veća nego za druge opisane oblike. Ipak, poseduje stabilnost u toku vremena koja je prilično kratka i, u svim slučajevima, manja od 6 meseci. This perfectly defined crystalline form, which is obtained in a reproducible manner, has highly valuable morphological characteristics with, in particular, a specific surface area that is much larger than for other described forms. However, it has a stability over time that is quite short and, in all cases, less than 6 months.

Podnosilac je sada razvio novi postupak za dobijanje agomelatina u kristalnom obliku V na savršeno reproducibilan način, gde je njegova stabilnost tokom vremena povećana. Ovaj novi postupak, prema tome, omogućava dobijanje agomelatina u kristalnom obliku V sa svojstvima koja su kompatibilna sa njegovom farmaceutskom upotrebom. Koristi se da bi se omogućilo dobijanje oblika V samo takozvanim “visoko-energetskim” mlevenjem ili putem zasejavanja te strukturno čiste forme koja se dobije mlevenjem. Podnosilac je sada otkrio, neočekivano, da je moguće dobiti ovaj oblik putem sušenja raspršivanjem. Sušenje raspršivanjem je zapravo tehnika koja se uobičajeno koristi za dobijanje čvrstih čestica u malim veličinama. Često, nastali materijal bude amorfan (Amorphous State, Polymorphism in pharmaceutical industry, Ed. R. Hilfiker, Wiley-VCH VVeinheim 2006, Chapter X, p. 259-285, S. Petit and G. Coquerel). Suprotno tome, u ovom pronalasku sušenje omogućava dobijanje dobro definisane kristalne forme, oblika V, koja pored toga ima, međutim, mnogo bolju stabilnost u toku vremena. The applicant has now developed a new process to obtain agomelatine in crystalline form V in a perfectly reproducible manner, where its stability over time is increased. This new procedure, therefore, allows obtaining agomelatine in crystalline form V with properties compatible with its pharmaceutical use. It is used to make it possible to obtain the V shape only by so-called "high-energy" grinding or by seeding the structurally clean form that is obtained by grinding. The applicant has now discovered, unexpectedly, that it is possible to obtain this form by spray drying. Spray drying is actually a technique commonly used to obtain solid particles in small sizes. Often, the resulting material is amorphous (Amorphous State, Polymorphism in pharmaceutical industry, Ed. R. Hilfiker, Wiley-VCH VVeinheim 2006, Chapter X, p. 259-285, S. Petit and G. Coquerel). Conversely, in the present invention, drying allows obtaining a well-defined crystalline form, the V-form, which in addition has, however, much better stability over time.

Preciznije, ovaj pronalazak se odnosi na novi postupak dobijanja agomelatina formule (I) u kristalnom obliku V, pri čemu se postupak odlikuje time da se rastvor agomelatina, koji je rastvoren u jednom ili dva rastvarača koja se mešaju u ma kom odnosu i čija je tačka ključanja manja od 120°C, atomizuje u sprej sušioniku. More precisely, this invention relates to a new process for obtaining agomelatine of formula (I) in crystalline form V, wherein the process is characterized by the fact that a solution of agomelatine, which is dissolved in one or two solvents that are mixed in a small ratio and whose point is boiling point less than 120°C, atomized in a spray dryer.

Sušenje raspršivanjem je tehnika koja se uobičajeno koristi u oblastima poljoprivrede, prehrane i farmacije kako bi se osušio rastvor koji se raspršuje kroz vruć gas. U praksi, gas koji se koristi za sušenje rastvora je vazduh ali izvesni farmaceutski proizvodni postupci koriste organske rastvarače koji pak zahtevaju inertni gas kao gas za sušenje i na taj način se izbegavaju izvesni procesi razgradnje. Spray drying is a technique commonly used in the fields of agriculture, food and pharmaceuticals to dry a solution that is sprayed through a hot gas. In practice, the gas used for drying the solution is air, but certain pharmaceutical production processes use organic solvents, which in turn require an inert gas as a drying gas, thus avoiding certain decomposition processes.

Postupci kristalizacije, koji su u skladu sa ovim pronalaskom, poželjno se izvode putem sušenja raspršivanjem. Još bolje, atomizacija u skladu sa pronalaskom se izvodi u skladu sa principom atomizacije putem raspršivača sa paralelnim strujnim tokom i poželjnije, sa ko-strujnim protokom, to jest, raspršenim rastvorom i protokom sušećeg gasa u istom smeru. Crystallization processes in accordance with the present invention are preferably carried out by spray drying. Even better, the atomization according to the invention is carried out according to the principle of atomization by means of a parallel current flow atomizer and more preferably, with a co-current flow, that is, the atomized solution and the drying gas flow in the same direction.

Pogodno, upotrebljeni gas je kompresovani vazduh ili inertni gas kao što je, na primer, azot. Suitably, the gas used is compressed air or an inert gas such as, for example, nitrogen.

Rastvarači koji imaju prednost u postupku koji je u skladu sa pronalaskom su: etanol, voda, izoprpoil etar, metanol, etil acetat ili aceton. Solvents that are preferred in the process according to the invention are: ethanol, water, isopropyl ether, methanol, ethyl acetate or acetone.

Minimalna koncentracija rastvora agomelatina koji se upotrebljava je 5 g/L a, poželjnije, koristi se rastvor od 10 g/L. The minimum concentration of the agomelatine solution used is 5 g/L and, more preferably, a solution of 10 g/L is used.

Pogodno, temperatura ulaza za postupak koji je u skladu sa pronalaskom je od 70°C do 120°C. Suitably, the inlet temperature for the process according to the invention is from 70°C to 120°C.

U procesu kristalizacije, koji je u skladu sa pronalaskom, moguće je upotrebiti agomelatin formule (I) koji se dobija ma kojim postupkom. In the crystallization process, which is in accordance with the invention, it is possible to use agomelatine of formula (I), which is obtained by any method.

Primeri u nastavku ilustruju pronalazak ali ga ne ograničavaju ni na koji način. The following examples illustrate the invention but do not limit it in any way.

Primer 1: Kristalni oblik V N-[2-(7-metoksi-1-naftil)etil]acetamida Example 1: Crystalline form V of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

10 g/L rastvora agomelatina u mešavini etanol/izopropil etra (50/50: v/v) unese se u atomizer BUCHI 190 tip Mini Spray Dryer. Temperatura ulaza komore za sušenje je 90°C, a temperatura izlaza je 66°C. Atomizirani prašak se dobija u crevu za sakupljanje i, opisuje se sledećim kristalografskim podacima: A 10 g/L solution of agomelatine in a mixture of ethanol/isopropyl ether (50/50: v/v) is introduced into the atomizer BUCHI 190 type Mini Spray Dryer. The inlet temperature of the drying chamber is 90°C, and the outlet temperature is 66°C. The atomized powder is obtained in a collection tube and is described by the following crystallographic data:

1) dijagramom, koji se dobija upotrebom difraktometra Siemens D5005 sa opsegom ugla 3°-30° u granicama od 20, korak od 0. 04° i 4 s po koraku: 1) diagram, which is obtained using a Siemens D5005 diffractometer with an angle range of 3°-30° within 20, a step of 0.04° and 4 s per step:

- kristalna struktura jedinične ćelije: monoklinska, - crystal structure of the unit cell: monoclinic,

- parametri jedinične ćelije: a = 11. 967 Å, b = 17. 902 Å, c = 15. 423 Å, β = 124. 5° - unit cell parameters: a = 11.967 Å, b = 17.902 Å, c = 15.423 Å, β = 124.5°

- prostor grupe: P2|/n - group space: P2|/n

- broj molekula u jediničnoj ćeliji: 8 (Z’=2) - number of molecules in the unit cell: 8 (Z'=2)

- zapremina jedinične ćelije: Vjedinične ćelije=2720.0 Å3 - unit cell volume: Unit cells=2720.0 Å3

2) sledeći dijagram difrakcije X-zraka praška, izmeren korišćenjem difraktometra Siemens D5005 (bakarna antikatoda) i izražen u granicama međupovršinske udaljenosti d, Braggovog ugla 2 teta i, relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju): 2) the following powder X-ray diffraction pattern, measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of interfacial distance d, Bragg angle 2 theta i, relative intensity (expressed as a percentage of the most intense line):

Primer 2: Stabilnost tokom vremena kristalnog oblika V, dobijenog atomizacijom N-[2-(7-metoksi-1 -naftil)etil]acetamida Example 2: Stability over time of crystalline form V obtained by atomization of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

Uzorak od 1 g jedinjenja dobijenog u Primeru 1 je smešteno pod uobičajene uslove skladištenja: pritisak i temperatura sredine. Nakon 21 meseca, difraktogram uzorka koji je dobijen se nije promenio i zadržao je karakteristike dobijenog oblika V. A sample of 1 g of the compound obtained in Example 1 was placed under the usual storage conditions: ambient pressure and temperature. After 21 months, the diffractogram of the obtained sample did not change and retained the characteristics of the obtained V shape.

Claims (11)

1. Postupak za industrijsku sintezu jedinjenja formule (I) koji je naznačen time što reaguje 7-metoksi-1-naftol formule (II): koji se kondenzuje, u prisustvu paladijuma, po prevođenju hidroksi funkcije u odlazeću grupu, kao što je halogen, tozilat ili trifluorometansulfonatna grupa, sa jedinjenjem formule (ili) : CH2=CH-R (III), gde R predstavlja grupu: gde R' i R", koji mogu biti isti ili različiti, svaki predstavlja linearnu ili razgranatu (C1- C6)alkil grupu ili, R' i R" zajedno obrazuju (C2-C3)alkilenski lanac i formirani prsten se može spojiti sa fenil grupom, kako bi se dobilo jedinjenje sa formulom (IV): gde je R, kao što je prethodno definisano, koje se podvrgava katalitičkoj hidrogenaciji da bi se dobilo jedinjenje formule (V): gde je R, kao što je prethodno definisano, koje se podvrgava hidrolizi bazom ili kiselinom ili binarnim sistemom redukujuće sredstvo/kiselina kako bi se dobilo jedinjenje sa formulom (VI) ili njegova hidrohloridna so: koje se sukcesivno podvrgava dejstvu natrijum acetata i zatim sirćetnog anhidrida da bi se dobilo jedinjenje formule (I), koje se izoluje u čvrstom obliku.1. Process for the industrial synthesis of compounds of formula (I) which is indicated by reacting 7-methoxy-1-naphthol of formula (II): which condenses, in the presence of palladium, after transferring the hydroxy function to a leaving group, such as a halogen, tosylate or trifluoromethanesulfonate group, with a compound of the formula (or) : CH2=CH-R (III), where R represents a group: where R' and R", which may be the same or different, each represents a linear or branched (C1-C6) an alkyl group or, R' and R" together form a (C2-C3)alkylene chain and the ring formed can be fused with a phenyl group to give a compound of formula (IV): where R is, as previously defined, which is subjected to catalytic hydrogenation to give a compound of formula (V): where R is as defined above, which is subjected to hydrolysis with a base or acid or a binary reducing agent/acid system to give a compound of formula (VI) or its hydrochloride salt: which is successively treated with sodium acetate and then with acetic anhydride to give the compound of formula (I), which is isolated in solid form. 2.Postupak za sintezu jedinjenja formule (I), kao u patentnom zahtevu 1, naznačen time što je jedinjenje formule (ili) N-vinilftalimid.2. Process for the synthesis of the compound of formula (I), as in claim 1, characterized in that the compound of formula (or) is N-vinylphthalimide. 3.Postupak za sintezu jedinjenja formule (I), kao u patentnom zahtevu 1, naznačen time što je jedinjenje formule (ili) akrilamid.3. Process for the synthesis of the compound of formula (I), as in claim 1, characterized in that the compound of formula (or) is acrylamide. 4.Postupak za sintezu jedinjenja formule (I), kao u patentnom zahtevu 1, naznačen time što se kondenzacija jedinjenja formule (III) da bi se dobilo jedinjenje formule (IV) izvodi upotrebom paladijum tetrakis(trifenilfosfina).4. Process for the synthesis of the compound of formula (I), as in claim 1, characterized in that the condensation of the compound of formula (III) to obtain the compound of formula (IV) is performed using palladium tetrakis(triphenylphosphine). 5.Jedinjenje formule (IV), kao u patentnom zahtevu 1, za upotrebu je kao intermedijer u sintezi agomelatina.5. The compound of formula (IV), as in claim 1, is for use as an intermediate in the synthesis of agomelatine. 6.Upotreba jedinjenja formule (IV), kao u patentnom zahtevu 5 u sintezi agomelatina.6. Use of the compound of formula (IV), as in patent claim 5, in the synthesis of agomelatine. 7.Upotreba jedinjenja formule (ll), kao u patentnom zahtevu 1 u sintezi agomelatina.7. Use of the compound of formula (ll), as in patent claim 1, in the synthesis of agomelatine. 8.Upotreba jedinjenja formule (V), kao u patentnom zahtevu 1 u sintezi agomelatina.8. Use of the compound of formula (V), as in patent claim 1, in the synthesis of agomelatine. 9.Postupak za sintezu agomelatina, kao u patentnom zahtevu 1, koji započinje od jedinjenja for ule (IV), naznačen time što se jedinjenje formule (IV) dobija sintetskim postupkom kao u bilo kom od patentnih zahteva 1 do 4.9. The process for the synthesis of agomelatine, as in patent claim 1, starting from the formula compound (IV), characterized in that the compound of formula (IV) is obtained by a synthetic process as in any of patent claims 1 to 4. 10.Postupak za sintezu agomelatina, kao u patentnom zahtevu 1, koji započinje od jedinjenja formule (V), naznačen time što se jedinjenje formule (V) dobija sintetskim postupkom kao u bilo kom od patentnih zahteva 1 do 4.10. The process for the synthesis of agomelatine, as in patent claim 1, which starts from the compound of formula (V), characterized in that the compound of formula (V) is obtained by a synthetic process as in any of patent claims 1 to 4. 11.Postupak za sintezu agomelatina, kao u patentnom zahtevu 1, koji započinje od jedinjenja formule (VI), naznačen time što se jedinjenje formule (VI) dobija sintetskim postupkom kao u bilo kom od patentnih zahteva 1 do 4.11. A process for the synthesis of agomelatine, as in claim 1, starting from a compound of formula (VI), characterized in that the compound of formula (VI) is obtained by a synthetic process as in any of claims 1 to 4.
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